Method and apparatus for connective tissue treatment

ABSTRACT

The invention relates to methods and apparatus for therapeutically treating connective tissue or increasing vascularization in tissue using ultrasound. More particularly, the present invention relates to methods and apparatus which use ultrasound to stimulate growth or healing, or to treating pathologies, of connective tissue, or to increase vascularization in ischaemic or grafted tissue using ultrasound.

This application is a continuation-in-part of, and claims priority to,U.S. Ser. No. 10/096,216, filed Mar. 11, 2002, now abandoned, which is acontinuation of Ser. No. 09/436,999, filed Nov. 9, 1999, now U.S. Pat.No. 6,355,006, which is a continuation of International ApplicationPCT/US98/02447, filed Feb. 6, 1998, which claims priority to U.S.Provisional Application No. 60/037,367 filed on Feb. 6, 1997. Thisapplication is a continuation-in-part of, and claims priority to, U.S.Ser. No. 09/568,481 filed May 9, 2000, now U.S. Pat. No. 6,432,070,which claims priority to U.S. Provisional Application No. 60/133,442,filed May 11, 1999, the entire contents of each of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods and apparatus fortherapeutically treating connective tissue and/or increasingvascularization in tissue using ultrasound. More particularly, thepresent invention relates to methods and apparatus which use ultrasoundto stimulate growth or healing, or to treating and/or preventingpathologies of connective tissue, or to increase vascularization inischaemic or grafted tissue using ultrasound.

2. Description of the Related Art

The use of ultrasound to therapeutically treat and evaluate boneinjuries is known. Impinging ultrasonic pulses having appropriateparameters, e.g., frequency, pulse repetition, and amplitude, forsuitable periods of time and at a proper external location adjacent to abone injury has been determined to accelerate the natural healing of,for example, bone breaks and fractures.

U.S. Pat. No. 4,530,360 to Duarte describes a basic non-invasivetherapeutic technique and apparatus for applying ultrasonic pulses froman operative surface placed on the skin at a location adjacent to a boneinjury. To apply the ultrasound pulses during treatment an operator mustmanually hold the applicator in place until the treatment is complete.

The Duarte patent as well as U.S. Pat. No. 5,520,612 to Winder et al.describe ranges of RF signal for creating the ultrasound, ultrasoundpower density levels, ranges of duration for each ultrasonic pulse, andranges of ultrasonic pulse frequencies.

U.S. Pat. No. 5,003,965 to Talish et al. relates to an ultrasonic bodytreatment system having a body-applicator unit connected a remotecontrol unit by sheathed fiber optic lines. The signal controlling theduration of ultrasonic pulses and the pulse repetition frequency aregenerated apart from the body-applicator unit. Talish et al. alsodescribes a mounting fixture for attaching the body-applicator unit to apatient so that the operative surface is adjacent the skin location.

While the systems described in these patents relate to therapeuticmethods and apparatus for ultrasonic treatment of hard and soft issueinjuries and defects, there is a need for ergonomically configuredsignal generators and transducers for the treatment of cartilage and/orosteochondral injuries and/or defects and/or for the treatment ofcartilage/degenerative joint diseases, such as osteoarthritis (OA).Further, a need exists for an apparatus which optimizes the treatment ofcartilage and/or osteochondral injuries and/or defects and/or thetreatment of cartilage/degenerative joint diseases, such asosteoarthritis.

A cartilage and/or osteochondral injury and/or defect and/ordegenerative joint disease, such as osteoarthritis, typically involvesdamage to the cartilage which lines articulating bones (articularcartilage), such as the bones of the knee, elbow, shoulder and ankle.Osteochondral injuries can be treated by chondral and/or osteochondraldrilling causing blood flow at the site. The aim of chondral drilling isto stimulate cartilage regeneration as part of the healing process.However, the resulting nonhyaline or fibrocartilage produced isbiomechanically inferior to articular cartilage, does not havecomparable proteoglycan content, and may consist primarily of a thinunorganized layer of collagen. Further, it has been observed thatdegeneration of the new tissue generally occurs over time, requiring theneed for additional reconstructive surgical treatment.

Other methods of treatment include: the transplantation of non-weightbearing cartilage to the injury and/or defect site; inducing a fractureat the injury and/or defect site; placing a carbon fiber matrix toinduce cartilage formation; and autologous chondrocyte implantation(ACI). ACI entails removing chondrocytes capable of regeneratinghyaline-like cartilage from the body and culturing them for severalweeks. During the culture process, the number of cells increasesapproximately 15 times that of the original tissue sample. The culturedcells are then transplanted through an arthrotomy. A small piece ofperiosteum, the skin covering a bone, is taken from the patient's tibia.The periosteum is then sutured over the defect to provide a protectivecover for the cultured cells. The cultured cells are injected under theperiosteum into the defect where they will continue to multiply andproduce a durable repair tissue. However, ACI increases the healing timesince the chondrocytes need to be cultured before they are transplantedto the patient.

Therefore, there is a further need for a method and apparatus tostimulate cartilage regeneration which produces a repair tissue that isfibrocartilage or hyaline-like, and which is equivalent to articularcartilage in mechanical properties. There is also a need for repairtissue that is generally superior in mechanical properties to thatgenerated using conventional techniques, as described above. Furtherstill, a need also exists for an apparatus which stimulates cartilageregeneration and where the regenerated cartilage does not degenerateover time requiring additional treatment or reconstructive surgery.Further, there is a need for an apparatus which stimulates cartilageregeneration and significantly reduces the healing time.

For treatment of degenerative joint diseases such as osteoarthritis,some combination of symptom-modifying drug, physiotherapy withnonsteroidal antiinflammatories (NSAID's), bracing, weight loss, and/orreduced activity are initially used. However, while these approaches maycontrol symptoms, they do not effectively address the underlying damageto connective tissue, such as cartilage. Moreover, the drugs used maycause severe side effects in some patients, which can result inhospitalization and, in some cases, death. It has been reported that anestimated 20,000 OA patients die each year in the United States fromgastrointestinal complications associated with NSAID use. If symptomsremain after these treatments, then more invasive treatment methods areoften used, such as injection of viscoelastic materials, arthroscopicsurgery, or total joint replacement. There remains a need for additionalmethods and apparatus that treat and repair connective tissue damage,e.g. damage to cartilage, rather than simply control symptoms ofosteoarthritis, and that do not have the side effects and/or toleranceproblems associated with current pharmaceutical therapies.

However, injuries and pathologies of cartilage are not the onlyconditions of connective tissue requiring treatment that involvesignificant healing time. When ligament and tendons rupture the patientshave pain and laxity of the joint or muscle. The current repair optionsavailable to the surgeon are to replace or reconstruct the damagedtissue with autograft or allograft tissue, augmentation of the tearsurfaces with a device, or by fixation of the tissue with devices suchas sutures or anchors, or to simply treat symptoms such as pain andinflammation, without resolving the underlying problem. Because of therisks associated with surgery, treatment options that do not necessarilyinvolve surgery would be desirable. In addition, the repaired tissue isoften not as strong as the original undamaged tissue, so that methods toincrease repair tissue strength and decrease rehabilitation time wouldalso be desirable. The success of therapies involving replacement orreconstructed tissue is often dependent on the body's ability tovascularize the tissue. Increased vascularization will lead to improved,faster healing, while insufficient vascularization can lead to necrosisof the tissue. Thus, methods for increasing vascularization insurgically repaired tissues would be advantageous.

In addition, in allograft or autograft replacement, the graft dies offand is subsequently repopulated and remodeled by infiltrating cells.This is a lengthy process during which time the graft loses strength andis at risk of rerupture or damage. This leads to lengthy rehabilitationtimes (e.g., a minimum of 6 months for anterior cruciate ligament (ACL)reconstruction). Inhibiting cell death within the graft via stimulationof blood vessel and tissue in-growth would therefore be desirable. Thiswill lead to a faster and stronger repair and reduced rehabilitationtime thus the patients will return to full function faster. Thephenomenon of “bone tunnel widening” can often present a problem.Improved integration of bone/tissue/ligament interfaces would help toavoid the “windshield wiper effect” posited as a mechanism for bonetunnel widening.

Surgical methods are also typically required to repair menisci in theknee, for example. Increased vascularization of the avascular “whitezone” of the menisci is desirable due to the stimulation in healing thatresults.

As explained above, the current treatments for many or most of theseconnective tissue injuries/pathologies are either surgical proceduresincluding repair, reconstruction, augmentation, fixation and tissueresection, or the use of drug therapies that reduce the pain andinflammation. These procedures are usually followed by (or combinedwith) rehabilitation including physiotherapy which will include a seriesof stretching exercises with a gradual increase in range of motion andloading on the repair tissue. However, physiotherapy is inconvenient,time consuming and relatively expensive, which can lead to problems withpatient compliance. There is thus a need in the art for methods ofspeeding healing and increasing vascularization that lend themselves touse by the patient at home, and do not require a significant amount oftime each day.

It is often desirable to address problems such as laxity of joints bymodifying tissues such that the collagenous components of connectivetissues (joint capsules, tendons, ligaments) are induced to contract, aprocedure often termed capsulorraphy. Applying thermal energy tocollagen can cause an alteration of the molecular configurationresulting in shrinkage. This results in a shorter structure and a‘tighter’ joint. However, the thermal energy incidentally may alsodamage the tissue resulting in loss of viability of cells, loss of bloodsupply and reduced mechanical integrity of the structure. Tissueshrinkage procedures have thus had difficulties resulting from decreasedbiomechanical integrity and long rehabilitation times due to slowhealing. This has resulted in the ‘modified’ tissue being stretched backout prior to its healing and reestablishment of normal biomechanicalstrength, resulting in the loss of the benefit of the shrinkageprocedure. This damage represents a significant disadvantage and hasinhibited the use of capsulorraphy and related tissue shrinkageprocedures. Faster post-shrinkage repair of tissue would minimize thesedifficulties and make the technique more widely applicable.

Tissue engineering involves the growth of cells on a scaffold in vitro(outside the body) to produce a graft for the repair of tissues withinthe body. One of the shortcomings of this approach is that it is notpossible to grow a tissue-engineered material (implant, graft or organ)with a vascular supply in vitro. When the tissue-engineered material isplaced into the body and stimulated with ultrasound functional bloodvessels are stimulated to grow into the tissue-engineered material fromthe hosts own blood supply. This is a means of vascularization of thisimplanted material thus retaining the function and viability of thegrafted material. There remains a need for methods and apparatus toachieve this vascularization of tissue engineered material.

SUMMARY OF THE INVENTION

The method and apparatus of the invention resolve many of thedifficulties associated with conventional therapies described above. Inone embodiment, the invention relates to a method for stimulating growthor healing, or treating pathologies, of connective tissue in mammals inneed thereof, by subjecting the affected connective tissue tononinvasive, low intensity ultrasound of a frequency and durationsufficient to stimulate growth, healing, or repair of the connectivetissue.

In another embodiment, the invention relates to a method for increasingvascularization in ischaemic or grafted tissue (not limited toconnective tissue) in mammals in need thereof, by subjecting theaffected tissue to noninvasive, low intensity ultrasound of a frequencyand duration sufficient to stimulate an increase in vascularization inthe ischaemic or grafted tissue.

In another embodiment, the invention relates to an apparatus foreffecting the treatment method described herein. The apparatus includesa placement module adapted to secure one or more transducers thereto ina plurality of configurations. The placement module is then secured to asite near the tissue in need of treatment, for example, at the knee,hip, ankle, shoulder, elbow, or wrist, and the transducers actuated toemit ultrasound sufficient to stimulate healing or repair, or toincrease vascularization. Further, the present invention also providesan embodiment having a placement module which contains a lockingstructure for locking in a particular position the articulating bones ofa joint undergoing treatment. This embodiment prevents the patient frommoving his limbs, for example, moving the femur with respect to thetibia, during treatment.

In another embodiment, the invention relates to an apparatus forpositioning one or more ultrasonic transducers with respect to a jointfor delivery of ultrasonic therapy thereto, having a covering memberadapted to cover at least a portion of the joint or adjacent bodymembers and be secured thereto in a fixed position, wherein the coveringmember comprises one more receiving areas adapted to receive and holdone or more ultrasonic transducer assemblies in one or more fixedpositions relative to the joint or adjacent body member.

Because of the broad applicability of utility of the invention inpromoting healing, the method and apparatus described herein are usefulin treating patients with a broad range of problems, such as trauma,tissue insufficiency, pain, post-surgical healing, degenerativeconditions such as osteoarthritis, and other problems. Moreover, becausethe invention is portable, does not require prolonged treatment times,and is designed for ease of use and positioning of the ultrasonictransducers, patients will be more likely to use the technique properlyand sufficiently to benefit therefrom.

BRIEF DESCRIPTION OF THE DRAWINGS

Specific embodiments of the invention are descried below with referenceto the drawings, which are described as follows:

FIG. 1 is a perspective view of a patient wearing one embodiment of aportable ultrasonic treatment apparatus suitable for carrying out themethod of the invention having a main operating unit or controller and aplacement module;

FIG. 2A is an exploded view of the placement module of the portableultrasonic treatment apparatus illustrated by FIG. 1;

FIG. 2B is a rear underside view of the placement module of the portableultrasonic treatment apparatus illustrated by FIG. 1;

FIG. 3 is a cross-sectional view illustrating a transducer assemblyaccording to one embodiment of the invention impinging ultrasonic wavesto connective tissue within the knee, with an ultrasonic conducting gelpositioned between the transducer assembly and the patient's knee;

FIG. 4 is a block diagram of one embodiment of the circuitry for oneembodiment of an ultrasonic transducer assembly;

FIG. 4A is a block diagram of an alternative embodiment of the circuitryfor the ultrasonic transducer assembly;

FIG. 5 is a perspective view of a second embodiment of the portableultrasonic treatment apparatus, illustrating a main operating unitcontroller and a placement module for treating connective tissueinjuries or pathologies within the elbow region;

FIG. 6 is a perspective view of a third embodiment of the portableultrasonic treatment apparatus, illustrating a main operating unitcontroller and a placement module for treating connective tissueinjuries or pathologies within the shoulder region;

FIG. 7 is a perspective view of a fourth embodiment of the portableultrasonic treatment apparatus illustrating a main operating unitcontroller and a placement module;

FIG. 8 is a perspective view of the portable ultrasonic treatmentapparatus illustrated by FIG. 7 mounted on a patient's ankle;

FIG. 9 is a perspective view of a fifth embodiment of the portableultrasonic treatment apparatus, illustrating a main operating unit orcontroller and a placement module for treating connective tissueinjuries or pathologies within the knee region;

FIG. 10A is an exploded view of the portable ultrasonic treatmentapparatus illustrated by FIG. 9;

FIG. 10B is a perspective view of a support member of the portableultrasonic treatment apparatus illustrated by FIG. 9;

FIG. 11A is a side view of an alternative embodiment of a placementmodule according to the invention;

FIG. 11B is a rear perspective view of the placement module of FIG. 11A;

FIG. 11C is a front view of the placement module of FIGS. 11A and 11B;

FIG. 12A is a left perspective view of another alternative embodiment ofa placement module according to the invention;

FIG. 12B is a right perspective view of the placement module illustratedin FIG. 12A;

FIG. 12C is an expanded perspective view of the placement moduleillustrated in FIGS. 12A and 12B;

FIG. 12D is a top view of the placement module illustrated in FIGS. 12Athrough 12C;

FIG. 13A is a left perspective view of another alternative embodiment ofa placement module according to the invention;

FIG. 13B is a right perspective view of the placement module illustratedin FIG. 13A;

FIG. 14 shows an embodiment of the placement module of the inventionsuitable for treating the shoulder area. FIG. 14A is a schematic view ofa placement module adapted to cover the torso area. FIGS. 14B and 14Care close up schematic views of open (14B) and closed (14C) transducerports;

FIG. 15A shows a schematic view of another embodiment of the placementmodule of the invention in the form of an adjustable shoulder brace.FIGS. 15B and 15C are close up schematic views of open (15B) and closed(15C) transducer ports;

FIG. 16 is a schematic view illustrating an embodiment of the placementmodule of the invention, wherein the covering member is a shoe orsneaker;

FIG. 17A is a schematic view of another embodiment of a placement modulesimilar in application to that of FIG. 16, but wherein the coveringmember is an elastic or stretchable. FIG. 17B is a close up schematicview of the transducer port or assembly;

FIG. 18A is a schematic view of an embodiment of a placement moduleaccording to the invention suitable for application of ultrasound to thewrist or hand area. FIG. 18B is a schematic exploded view of thetransducer port or assembly;

FIG. 19 is a schematic view of an embodiment of a placement moduleaccording to the invention suitable for application of ultrasound to theelbow area.

FIG. 20A is a photomicrograph of ovine tendon graft after 3 weekswithout treatment according to the invention;

FIG. 20B is a photomicrograph of ovine tendon graft after 3 weeks ofultrasonic treatment according to the invention;

FIG. 21A is a photomicrograph of ovine tendon graft after 6 weekswithout treatment according to the invention;

FIG. 21B is a photomicrograph of ovine tendon graft after 6 weeks withultrasonic treatment according to the invention;

FIG. 21C is a photomicrograph of an intra-articular section of the ovinetendon graft shown after 6 weeks with ultrasonic treatment according tothe invention;

FIG. 21D is a photomicrograph of bone marrow near an ovine tendon graftafter 6 weeks with ultrasonic treatment according to the invention;

FIG. 22A is a photomicrograph of an intra-articular section of ovinetendon graft after 12 weeks without treatment;

FIG. 22B is a photomicrograph of an intra-articular section of ovinetendon graft after 12 weeks with ultrasonic treatment according to theinvention;

FIG. 22C is a photomicrograph of ovine tendon graft after 12 weekswithout treatment;

FIG. 22D is a photomicrograph of ovine tendon graft after 12 weeks withultrasonic treatment according to the invention.

FIG. 23A is a photomicrograph of tissue from an ultrasound treated kneejoint in a guinea pig having osteoarthritis.

FIG. 23B is a photomicrograph of tissue from a control knee joint in aguinea pig having osteoarthritis.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

The ultrasonic treatment apparatus and method of the present inventioninvolves the non-invasive use of low intensity, ultra high-frequencyacoustic energy (ultrasound) to treat injuries, defects, or pathologiesof connective tissue, or to increase vascularization of ischaemic orgrafted tissue. It will be recognized that in treating connectivetissue, increased vascularization will likely result and contribute tohealing, but that the use of the method and apparatus to increasevascularization is not limited to treatment of connective tissue, butextends to grafted tissues, organs, or engineered tissue that has beenproduced ex vivo.

As described above, in one embodiment, the invention relates to anapparatus and method for the treatment of injuries and pathologies, andthe stimulation of healing, of connective tissues. The method may beused as an adjunct to surgical repair, in order to speed healing, or insome cases can be used alone to heal tissue injuries without surgery(e.g., for degenerative diseases such as osteoarthritis, tendonosis, andtendonitis). The apparatus and method of the invention are particularlysuitable for use in treatment of connective tissues associated withjoints, such as those in the hand or foot, wrist, ankle (Achillestendon), knee (e.g., anterior cruciate ligament, posterior cruciateligament, meniscofemoral ligament, lateral or collateral ligaments,tendon of quadriceps, gracilis tendon, sartorius tendon, semitendinosisto tendon, popliteus tendon, adductor magnus tendon, medial or lateralmeniscus), elbow (lateral, collateral, or annular ligaments), hip,shoulder (e.g., supraspinatus tendon/rotator cuff/glenoidal labrum),back and neck.

Nonlimiting examples of conditions or situations in which treatmentaccording to the invention is suitable include degenerative diseasessuch as osteoarthritis, ligament, tendon, spinal disc and meniscusinjuries, ligament and tendon pathologies, surgical repair ormodification (including modification procedures such as capsulorraphy(shrinkage), and procedures for shrinkage of the spinal disc (forexample the Idet procedure), and for the treatment of ischaemic tissues(such as a myocardially infarcted heart) to increase vascularization byinducing a vascular supply (in-growth of new blood vessels) into thesetissues (used herein to refer to tissues that have either a restrictedblood flow or a lack of adequate vascular supply). The invention couldalso be used to increase vascularization in a grafted tissue/organ orinto a tissue engineered graft that has been produced ex vivo.

The invention can be used as an adjunct to the surgical repair ofruptured ligament and tendons (for example rotator cuff tendon repair,anterior cruciate ligament, posterior cruciate, lateral collateralligament, medial collateral, flexor or extensor repairs, Achillestendon, surgical tendon transfers or tendon weaves).

The invention is suitable for treatment of a number of differenttendoniopathies and/or overuse injuries, including without limitationlateral or medial epicondylitis (tennis elbow), carpal tunnel syndrome,plantar fascitis, Achilles tendonitis, and the like, as either anadjunct to surgery, or without surgery.

The invention can also be used to increase the rate, quality andvascularity of connective tissue that is regenerated on, and/or growsinto, a scaffold which is implanted into the body to support connectiverepair/regrowth. The term “scaffold” as used herein means a threedimensional, at least partially porous structure, and having sufficientporosity to allow cell infiltration. The scaffold surface allows celladhesion and growth such that cell proliferation and extracellularmatrix (ECM) generation can occur and tissue can be laid down andremodel.

The scaffolds can be formed from bioresorbable or non-bioresorbablematerials. Suitable bioresorbable materials include bioresorbablepolymers or copolymers including, for example, polymers and/orcopolymers formed from the following monomers or mixtures thereof:hydroxy acids, particularly lactic acid, glycolic acid; caprolactone;hydroxybutyrate; dioxanone; orthoesters; orthocarbonates; and/oraminocarbonates. The bioresorbable materials may also contain naturalmaterials such as collagen, cellulose, fibrin, hyaluronic acid,fibronectin, chitosan or mixtures of two or more of these materials. Thebioresorbable materials may also contain devitalised xenograft and/ordevitalised allograft material. Bioresorbable ceramics, such mono-, di-,octa-, a-tri-, b-tri and tetra-calcium phosphate, hydroxyapatite,fluoroapatite, calcium sulphate, calcium fluoride, calcium oxide ormixtures of two or more of these materials, may also be used as scaffoldmaterial.

Suitable non-bioresorbable materials for use in scaffolds includepolyesters, particularly aromatic polyesters, such as polyalkyleneterephthalates, like polyethylene terephthalate and polybutyleneterephthalates; polyamides; polyalkenes such as polyethylene andpolypropylene; poly(vinyl fluoride), polytetrafluoroethylene carbonfibres, silk (natural or synthetic), carbon fibre, glass and mixtures ofthese materials.

Scaffolds may also be formed from materials that include hydrogels.Examples of suitable hydrogel materials include:poly(oxyethylene)-poly(oxypropylene) block copolymers of ethylenediamine, polysaccharides, chitosan, poly(vinyl amines), poly(vinylpyridine), poly(vinyl imidazole), polyethylenimine, poly-L-lysine,growth factor binding or cell adhesion molecule binding derivatives,derivatised versions of the above, e.g. polyanions, polycations,peptides, polysaccharides, lipids, nucleic acids or blends,block-copolymers or combinations of the above or copolymers of thecorresponding monomers; agarose, methylcellulose,hydroxypropylmethylcellulose, xyloglucan, acetan, carrageenan, xanthangum/locust bean gum, gelatine, collagen (particularly Type 1),PLURONICS™, POLOXAMERS™, poly (N-isopropylacrylamide) andN-isopropylacrylamide copolymers.

Structurally, the scaffold may be a woven, non-woven (fibrous material),knitted, braided or crocheted material, a foam, a sponge, a dendriticmaterial, or a combination or mixture of two or more of these.

Following surgery, the ultrasound device is applied non-invasively tothe outside of the body (e.g., coupled to the skin with coupling media,such as a gel) after surgery in the region of the repaired tissue, andis operated to transmit ultrasound, desirably in the form of pulses,into the tissue in need of treatment, or at the interface with theuninjured tissues. Exposure to the ultrasound stimulates a faster,better quality repair of the tissue. At a bone interface, the ultrasoundwill also stimulate bone repair and bone in growth into the repair orgraft tissue. This gives rise to a faster, stronger repair and improvedintegration of the interface between, e.g., tendon, ligament and bone.

The method and apparatus of the invention may also be used tonon-invasively treat pathologies of connective tissues, such asosteoarthritis, ligament and tendon conditions, without the need for asurgical procedure. Such conditions include, as examples,osteoarthritis, acute tears, chronic overuse injuries, and tendonpathologies including tendonosis and tendonitis. In these cases thedevice would be applied to the skin in the region of pain above theinjured or degenerative tendon or ligament. The ultrasound would thenpropagate in to the defective tissue and stimulate the tissue to remodeland repair without the requirement for surgery. The treatment thus wouldimprove the in-vivo function of the tissue with respect to mechanicalload bearing, and avoid the risks and disadvantages associated withsurgery, as described above.

As described above, the method and apparatus of the invention is alsoparticularly suitable for stimulating repair of damaged menisci. Thiscould be done after surgical repair to stimulate the healing process, oras a possible alternative to surgery. Without being bound by any theory,the invention appears to be particularly useful because it stimulateshealing of the avascular ‘white zone’ of the meniscus by stimulatingin-growth of blood vessels and their concomitant cell populations, whichare capable of healing the damaged tissue. More particularly, themeniscal cartilage is partially vascularized in the external peripheryof the tissue and has an avascular inner region. If the vascular regionis damaged, it usually heals or can be repaired due to the presence of ablood supply. If the avascular region is damaged, it does not heal andcannot be easily repaired because of the absence of blood supply. As aresult, damaged avascular regions often must be resected, which can leadto post meniscectomy arthritis. However, using the method and apparatusof the invention repair of the avascular region becomes possible due tothe ability of the invention to stimulate vascularization.

However, the method and apparatus of the invention is not limited toincreasing vascularization of damaged menisci, but can also be used totreat general ischaemic tissues which have restricted blood flow and/ora lack of adequate vascular supply. For instance, the method andapparatus of the invention can be used to induce a vascular supply andin growth into a grafted tissue or organ, or into a tissue engineeredgraft that has been produced ex vivo and pro lacks a vascular supply.The invention could also be used to treat tissues with a partialvascular supply to stimulate repair of tissues in the avascular regionof the tissue.

In addition to surgical and nonsurgical treatment of tissue injuries,defects, or pathologies, the method and apparatus of the invention canalso be used as an adjunct to tissue modification treatments, such ascapsulorraphy, or shrinkage of the spinal disc and related or similartissue shrinkage procedures, to significantly increase the success rateand benefit to the patient of undergoing such procedures. As describedabove, the use of thermal energy to alter the configuration ofconnective tissue and thereby eliminate joint laxity is associated withproblems relating to tissue damage. Loss of cell viability, loss ofblood supply, and reduced mechanical integrity can result in loss ofmany of the benefits associated with the tissue shrinkage procedure.

The method and apparatus of the invention provides a means to addressthese potentially adverse effects by stimulating revascularization andcell repopulation, resulting in repair and return to normalbiomechanical integrity. The invention adds to the ability to shrink thetissue the ability to also rapidly heal it in its shortenedconfiguration, and as a result offers a new treatment option that waspreviously difficult to achieve. This invention thus makes practical anew treatment method having the significant benefits associated with areduced surgical procedure, i.e. a less invasive and traumaticprocedure, for otherwise difficult to treat cases. The reduction inhealing time obtainable with the method and apparatus of the inventionmeans that that the chances of the weakened tissue being stretched arereduced. The reduction in rehabilitation time allows the patient toreturn to normal activities more quickly. The combination of a minimallyinvasive procedure using radiofrequency tissue shrinkage technology incombination with the method and apparatus of the invention provides aprocedure offering dramatically reduced rehabilitation time and anopportunity to treat a broader range of patients and disorders withoutsurgery.

The method and apparatus of the invention can be combined withpharmacological treatment modes, and these combinations also form a partof the invention. For instance, the method of the invention can be usedin conjunction with known growth factor therapies, including but notlimited to, the Transforming Growth Factor β superfamily, including:TGFβ's, Bone Morphogenetic Proteins (BMP's, e.g. BMP2, BMP4), CartilageDerived Morphogenic Proteins (CDMP's e.g. CDMP-1, CDMP-2) and GrowthDifferentiation Factors (e.g. GDF5), angiogenic factors (angiogenin),platelet-derived cell growth factor (PD-ECGF), Platelet Derived GrowthFactors (PDGF), Vascular Endothelial Growth Factor (VEGF), the EpidermalGrowth Factor family, e.g. EGF, Transforming Growth Factor Alpha (TGFα),Platelet Derived Growth Factors, e.g. PDGF-A, PDGF-B, PDGF-BB,Fibroblast Growth Factors, e.g. BFGF, Hepatocyte Growth Factors (HGF),Insulin-like Growth Factors, e.g. IGF-1, IGF-II, Growth Hormones (GH),Interleukins (e.g. IL-1, IL-11), Connective Tissue Growth Factors(CTGF), Parathyroid Hormone Related Proteins (PTHrp), autologous growthfactors (such blood and platelet derived factors), and mixtures of atleast two of these materials. In conjunction with growth factortherapies, the method and apparatus of the invention provide a faster,better quality repair. Appropriate dosages of such growth factors arethose known in the art for use in therapy without ultrasound treatment.

As described in more detail below, the apparatus of the inventioncontains one or more ultrasound treatment heads that direct ultrasonicenergy to the site of the tissue to be treated through the overlyingtissues. Without being bound by any theory, it is believed that theultrasonic energy provides a mechanical stimulus that induces tissuerepair and also stimulates blood vessel in growth and blood flow to thetissue which aids the healing or repair process. This stimulationappears to be the result of a molecular mechanism related to vascularitythrough an increase in growth factor and biological molecules known tobe vital for angiogenesis, matrix production and cellular proliferation.The pathway may be mediated through signal transduction molecules thatregulate cellular function.

The ultrasound is generally a low intensity ultrasound having afrequency ranging between about 1 and about 2 MHz, more particularlyabout 1.5 MHz. The ultrasound desirably is pulsed, having a pulse widthranging from about 10 to about 2,000 microseconds, more particularlyabout 200 microseconds, with a repetition frequency ranging from about0.1 to about 10 KHz, more particularly about 1 KHz.

The ultrasonic energy is emitted by one or more transducers. Multipletransducers are often desirable, in particular for treating some typesof ligament injury, and when present can be configured into arrays toproperly place them adjacent to areas to be treated. For example ACLsurgical repairs can be treated with multiple transducers, each in aseparate treatment head. One treatment head is applied to the outside ofthe knee in the region of the tibial bone tunnel; another treatment headis applied to knee in the region of the mid section of the graft andanother treatment head is applied to knee in the region of the femoralbone tunnel. Multiple transducers can also be set to emit energysimultaneously (e.g., in simultaneous pulses) or in a phased fashion,such that they emit pulses sequentially.

One embodiment of the apparatus of the invention includes anergonomically constructed placement module having a strap or otherfastening means for securing it and the attached transducer or treatmenthead adjacent to the part of a patient's body in need of treatment. Atleast one ultrasonic transducer assembly is attached or imbedded withinthe placement module and properly positioned on the various anatomicalregions in proximity to the desired treatment site. Different types ofultrasonic transducers and signals can be provided, such as thosedescribed and schematically depicted in U.S. Pat. No. 5,520,612 toWinder et al., which is incorporated herein by reference. Thetransducers described in U.S. Pat. No. 5,520,612 produce ultrasoundhaving an intensity less than 100 milliwatts/cm². Particularly, thetransducers and arrangements schematically depicted by FIGS. 7-11 of thepatent in which at least one transducer is used to provide acousticenergy to the site of the injury. The apparatus may also utilize aportable, ergonomically constructed main operating unit (MOU), which maybe worn by the patient, and which provides control signals to theultrasonic transducer(s). An example of a suitable MOU is that describedin U.S. Pat. No. 5,556,372 to Talish et al. which is incorporated hereinby reference.

Turning to the figures, in particular FIG. 1, one embodiment of theportable ultrasonic treatment apparatus 10 useful in accordance with theinvention is shown. The ultrasonic treatment apparatus 10 includes a MOU12, a placement module 14, and ultrasonic transducer assembly ortreatment head 16.

The placement module 14 comprises a placement support 20 which includesat least two or three channels 22 each having an extension 24 mountedtherein. Each extension has a transducer pocket 26 at one end or holdingone ultrasonic transducer assembly 16. It is contemplated for eachextension 24 to have several range of movements besides longitudinalmotion, such as articulating to the longitudinal motion.

The placement module 14 further includes a placement band 28 cooperatingwith slot 30 for securing the placement support 20 to the patient. Theplacement band 28 is configured to firmly secure the placement module 14to the patient. A sponge-like material 32 can be used to line the innersurface of the placement support 20 for providing comfort to the patient(FIGS. 2A and 2B). The placement support 20 may be constructed of hardplastics which may be custom molded for a particular body part of thepatient.

With reference to FIGS. 2A and 2B, the extensions 24 are mounted to theplacement support 20 via screws 33 and thumb screws 34. The screws 33are passed through slots 35 and holes 36 on the extensions 24 and arethreaded to the thumb screws 34. The extensions 24 can be moved todifferent positions to accommodate patients of all sizes by unthreadingthe thumb screws 34 and shifting the screws 33 along the slots 35 andthreading the screws 33 to the thumb screws 34 at the new position.

The transducer assembly 16 may include circuitry, schematicallyillustrated by FIGS. 4 and 4A and described below, for exciting theleast one transducer therein and is coupled to the MOU by cable 37 andwires 39. The wires 39 are coupled to the placement support 20. Thecable 3 is preferably a multiconductor cable capable of transmittingrelatively low frequency RF or optical signals, as well as digitalsignals. The cable 37 may include coaxial cable or other types ofsuitable shielded cable. Alternatively, the cable 37 may include fiberoptic cable for transmitting optical signals. The signals may betransmitted continuously or as a series of pulses.

In operation, the placement module 14 is positioned and secured to thepatient's body as shown by FIG. 3, such that each transducer assembly 16lies over the treatment site. A locating ring such as the one disclosedin U.S. patent application Ser. No. 08/389,148, incorporated herein byreference, may be used for determining the location of injured bone, ifthe patient desires to have one of the transducer assemblies overlying abone injury, before the placement module 14 is secured to the patient.Once the placement module 14 is properly positioned, the transducerwithin the transducer assembly 16 is excited for a predetermined amountof time. An ultrasound conducting gel 38 is positioned between thetransducer assembly 16 and the injured part of the patient's body toprevent attenuation of the ultrasonic waves as they travel to theconnective tissue 40, as shown by FIG. 3.

It is also contemplated that one or more transducers can be converted toreceive reflected diagnostic data from the treatment site. This permitsreal time evaluation of the injury site and healing process.

With reference to FIG. 4, a block diagram of one embodiment of theultrasonic transducer assembly circuitry is shown. The transducerassembly circuitry 17 includes a receiver/RF oscillator 50 whichreceives the signals transferred by a signal generator within MOU 12 viacable 37. The receiver/RF oscillator 50 is connected to transducerdriver 52 which excites transducer 16. An alternative embodiment of thetransducer assembly circuitry 17 is shown in FIG. 4A. In thisembodiment, the ultrasonic transducer assembly 16 includes an internalbattery 60 which supplies power to the components within the transducerassembly 16. For example, battery 60 supplies power to signal monitoringcircuit 62 and signal driver 66. The signal monitoring circuit 62provides, preferably, a digital output signal 68 which represents thewaveform characteristics of the output of transducer driver 70. Thesecharacteristics can be displayed on a digital display and may include,for example, the frequency, pulse repetition frequency, the pulse widthand the average output power of the transducer 16. The output signal 68of signal monitoring circuit 62 is transferred to the signal generatorwithin MOU 12 via driver 66 and cable 37. The signal generator mayinclude a processor and a switch for regulating the signalcharacteristics. Control signals from the MOU 12 are received byreceiver 72 via cable 37. Safety or fixture interlock 74, which mayinclude switches on the outer surface of the placement module 14 ortransducer assembly 16, ensures that the placement module 14 is properlypositioned before providing power to the internal components of thetransducer assembly 16.

A second embodiment of the portable ultrasonic treatment apparatus ofthe present invention is illustrated by FIG. 5 and designated generallyby reference numeral 200. The treatment apparatus 200 includes MOU 12and transducer assemblies 202 affixed to a placement module 204 viaextensions 206 for ultrasonically stimulating the repair or healing oftissue in the elbow region. Each transducer assembly 202 includes apower transducer 212 connected to the MOU 12 by cable 218. An ultrasonicconducting gel 212 is positioned between the transducer assemblies 202and the treatment site to prevent attenuation of the ultrasonic waves asthey travel to the tissue being treated. In order to accommodate variouspatients, the extensions 206 can be adjusted to several positions byunthreading thumb screws 220. The circuitry for each transducer assembly202 may be similar to that disclosed for the first embodiment andschematically illustrated by FIGS. 4 and 4A.

It is envisioned that the placement module 204 b constructed fromsuitable conductive plastics, such as conductive ABS plastics witheither carbon, stainless steel, nickel or aluminum fibers to forego theuse of wires for connecting the transducer assemblies 202 to the cable218. In such an embodiment, the conductive placement module 204 would beused to electrically connect the transducer assemblies 202 to the MOU 12via cable 218.

With reference to FIG. 6, a third embodiment of the portable ultrasonictreatment apparatus of the present invention is illustrated. In thisembodiment, the treatment apparatus 300 includes a MOU 12, a placementmodule 304, and ultrasonic transducer assemblies 306. The placementmodule 304 is configured for placement on the shoulder region andincludes a placement band 310 and a placement support 312. Eachtransducer assembly 306 is connected to the MOU 12 by cable 318 to powertransducer assembly circuit within each assembly 306. The circuitry (notshown) may be similar to that disclosed for the first and secondembodiments and to schematically illustrated by FIGS. 4 and 4A.

In operation, transducers within transducer assemblies 306 are excitedfor a predetermined period of time to impinge ultrasonic waves toarticular cartilage within the shoulder region.

A fourth embodiment of the portable ultrasonic treatment apparatus ofthe present invention which is primarily suitable for the treatment ofconnective tissue is illustrated by FIGS. 7 and 8. In this embodiment,the apparatus 400 includes at least one ultrasonic transducer assembly402 positioned within pockets 404 on a strip 406. The transducerassemblies 402 may be arranged in a plurality of configurations withinpockets 404 to accommodate many patients' anatomical differences. Thestrip 406 is secured in proximity to the desired treatment site as shownby FIG. 8 by a self-tieing material 405. The strip 406 is connected iswires 407 and cable 408 to a MOU 12 which contains circuitry forexciting the at least one ultrasonic transducer assembly 402 affixed tothe strip 406.

In operation, at least one transducer assembly 402 is excited to impingeultrasonic waves to the treatment site as shown by FIG. 8. It iscontemplated that during treatment an ultrasonic conducting gel ispositioned between the strip 406 and the patient's body to preventattenuation of the ultrasonic waves.

It is also contemplated to manufacture the strip 406 from suitableconductive plastics such as conductive, ABS plastics with either carbon,stainless steel, nickel or aluminum fibers to forego the use of wiresfor electrically connecting the at least one ultrasonic transducer 402to the cable 408.

A fifth embodiment of the portable ultrasonic treatment apparatus of thepresent invention which is primarily suitable for the treatment ofconnective tissue is illustrated by FIGS. 9-10B. In this embodiment, theapparatus 500 includes a MOU 12 and three ultrasonic transducerassemblies 502 positioned within pockets 504 on an inner surface of aconcave plate 506 as shown by FIG. 10B. The concave plate 506 ispositioned at one end 30 of a vertical bar 508 having a slot 509 at alower portion. The apparatus 500 further includes a locking supportmodule 510 having a thigh support 512 and a leg support 514.

As shown by the exploded view of FIG. 10A, the high support 512 includesa thigh support plate 516, a securing band 518, and two horizontallocking extensions 520 affixed to the thigh support plate 516 by crews522 and thumb screws 524. The leg support 514 includes a leg supportlate 526, a securing band 528, and two vertical locking extensions 530affixed to the leg support plate 526. The vertical bar 508 is configuredto mount within a channel 532 on the leg support 514. The vertical bar508 is secured to the channel 532 by screw 534 and thumb screw 536. Thevertical bar 508 can be moved vertically along the channel 532 byunthreading the thumb screw 536 to accommodate various patients.

The thigh support 512 and the leg support 514 are locked to each otherby locking the horizontal locking extensions 520 and the verticallocking extensions 530 by screws 538 and thumb screws 540 to prevent thepatient from moving the thigh with respect to the leg during treatmentand to ensure that the transducer assemblies 502 remain fixed in theirproper positions. The transducer assemblies 502 are connected via acable 542 which is plugged in to hole 544 to the MOU 12 which containscircuitry for exciting the ultrasonic transducer assemblies 502. It iscontemplated that during treatment an ultrasonic conducting gel ispositioned between the transducers 502 mounted in concave plate 506 andthe patient's body to prevent attenuation of the ultrasonic waves.

Alternative embodiments of the placement module described above alsoform a part of the invention, and are illustrated in FIGS. 11-19. Theseembodiments of placement module generally contain a covering member,which covers or surrounds a part of the joint or associated limbs orother adjacent anatomical structures, and provides attachment points forultrasonic transducers or assemblies containing ultrasonic transducers.The covering member, while adjustable, is intended to remain in a fixedposition once disposed on or around the joint, and its attachment pointsprovide a frame of reference for appropriately positioning theultrasonic transducer or assembly to direct the ultrasound toward thetreatment site. While the embodiments illustrated herein arespecifically adapted for use with the human knee, and more specificallyadapted to provide ultrasound therapy to the ACL area, it will berecognized that these embodiments are not so limited in application, andcan be readily used or adapted for use with other joints, or to treatother connective tissue within the knee.

FIGS. 11A, 11B, and 11C illustrate an embodiment of placement module 600having covering member 602 secured to the underside of the knee by upperand lower securing straps 604 and 606, respectively. Covering member602, which may be flexible (e.g., a fabric) or rigid (e.g., a plastic)contains receiving areas 608, 610, which are adapted to receiveultrasonic transducer assemblies 612, 614. These are illustrated asstraps containing ultrasonic transducer ports 616, 618, and which can besecured to covering member 602 by hook-and-loop fabric (e.g., VELCRO).As used herein, the term “ultrasonic transducer assembly” means anassembly capable of receiving and holding an ultrasonic transducer, withor without the transducer attached thereto. By positioning thetransducer assemblies properly at their attachment points on thecovering member, the ultrasonic transducers will be appropriatelypositioned to direct ultrasound to the area of the surgery ordiscomfort.

FIGS. 12A, 12B, 12C, and 12D illustrate another embodiment of placementmodule 700 according to the invention. Covering member 702, which may beeither rigid or flexible covers the front of the knee, and is secured tothe legs by straps 704 and 706. Covering member 702 contains receivingareas 708, 710, which are adapted to receive ultrasonic transducerassemblies 712, 714, which contain ultrasonic transducer ports 716, 718.In the embodiment illustrated, placement module 700 also contains rigidstrut 720, which adjusts to hold the joint in a predetermined position.As best seen in FIG. 12C, rigid strut 720 can be provided withadjustability by locking hinge or pivot 722, which is fitted withlockout gears 724, as well as with optional D-ring 726, which allows forthe use of an optional strap for added security or an additionalultrasonic transducer assembly. As with the placement module illustratedin FIG. 11, the ultrasonic transducer assemblies 712, 714 are strapsthat, like the securing straps 704, 706 are secured to the coveringmember with hook and loop closures.

FIGS. 13A and 13B illustrate yet another embodiment of placement module800 having covering member 802, made from a flexible, elastic fabricthat surrounds the knee and surrounding portions of the leg. Receivingareas 808, 810 are disposed in the fabric itself, so that an ultrasonictransducer can be inserted directly therein. The elastic material holdsthe transducers in position and directs the ultrasound toward the ACLtreatment site.

FIG. 14A illustrates another embodiment of placement module 900,illustrated as a fabric shirt (forming covering member) 902 that can beworn over the torso. The shirt has a transducer port 904 (one isillustrated, but multiple ports may be present). FIG. 14B is a schematicdiagram showing a close-up view of transducer port 904, whereintransducer port cap 908 is in the closed position. FIG. 14C is aschematic diagram showing transducer port cap 908 in the open position,so that transducer 906 is visible (similar ports can be used with theembodiments shown in the other figures). The covering member or fabricshirt 902 can be made from an elastic or stretchable fabric, such asSpandex or the like, to hold the transducer port next to the skin of thepatient.

FIG. 15A illustrates another embodiment of placement module 900 in theform of an adjustable shoulder brace. Covering member 902 can be made ofan elastic or stretchable material to hold transducer port 904 firmlyagainst the skin. Covering member 902 can be secured in place byretaining strap 910, which can be disposed around the torso and securedvia one or more attachment point, 912. Retaining strap 910 and coveringmember 902 may form an integral piece that wraps around the body, or maybe formed from two separate pieces of fabric having two attachmentpoints. As with the embodiment shown in FIG. 14, the shoulder braceshown in FIG. 15A is well adapted to provide ultrasonic treatment toconnective tissue in the shoulder area. The embodiment of transducerassembly or port 904 illustrated in FIG. 15B and FIG. 15C is describedabove with respect to FIG. 14B and FIG. 14C.

FIG. 16 illustrates an embodiment of placement module 900, wherein thecovering member 902 is a shoe or sneaker having transducer assembly orport 904 attached thereto. As illustrated, the placement module 900 isparticularly adapted to supply ultrasound to tissue in the area of theankle, e.g., for repair or healing of Achilles' tendon injuries.However, transducer assembly or port 904 could be readily placed inother areas of the shoe or sneaker to apply ultrasound to other parts ofthe ankle or foot.

FIG. 17A illustrates another embodiment of placement module 900, similarin application to that of FIG. 16, but wherein the covering member 902is an elastic or stretchable fabric holding transducer port or assembly904 in place firmly against the skin. As with the embodiment shown inFIG. 16, placement of the transducer port or assembly can be varied toapply ultrasound to different tissues in the foot or ankle. Theembodiment of transducer assembly or port 904 illustrated in FIG. 17B isdescribed above with respect to FIG. 14C.

FIG. 18A illustrates an embodiment of placement module 900 suitable forapplication of ultrasound to the wrist or hand area. Covering member 902forms an adjustable strap that encircles the wrist and holds transducerport or assembly 904 against the skin of the patient. The embodiment oftransducer assembly or port 904 illustrated in FIG. 18B is describedabove with respect to FIG. 14C.

FIG. 19 illustrates an embodiment of placement module 900 suitable forapplication of ultrasound to the elbow area. Covering member 902 is anelastic or stretchable fabric holding transducer port or assembly 904 inplace firmly against the skin. Although illustrated disposed on theouter side of the elbow, the transducer port or assembly 904 can bedisposed along the inner surface of the elbow if desired.

Example 1

An ovine model of soft tissue graft (digital extensor tendon)reconstruction of the ACL was utilized to allow for assessment of themethod and apparatus of the invention. A modified ACL reconstruction wasperformed on 21 animals in three groups of 7 animals. Control groups of2 animals (provided with no ultrasound treatment), and experimentalgroups of 5 animals (provided with ultrasound treatment for 20 minutescontinuously each day) were harvested at the end of 3, 6, and 12 weeks.

The right hind limb was operated on in all animals. The anteriorcruciate ligament (ACL) was visualized and removed at the insertion sitethrough an antero-medial arthrotomy. The ACL reconstruction wasperformed using a digital extensor tendon graft. The tendon graft washarvested from the same limb by 2 stab incisions. The graft was whipstitched using # 2 Ethibond and prepared using the Acufex Graftmaster.The graft was doubled and passed through 4.5 mm tunnels in the tibia andfemur. Endobutton fixation was used on the femoral side with tibialfixation over a bony post. The surgical incisions were then closed usingstandard suturing techniques. The animals were then recovered andultrasound treatment was initiated on the members of the experimentalgroup one day following surgery.

The animals in the treatment groups were treated with pulsed lowintensity ultrasound (1.5 MHz, pulsed at 1 KHz, 200 μs burst width) for20 minutes per day for the duration of the study. Ultrasound deviceshaving two ultrasound transducers were used. One transducer was coupledto the skin (wool was shaved) over the femoral bone tunnel containingthe graft, while the other was coupled to the skin over the tibialattachment tunnel. The transducers were held in place during treatmentwith strapping.

Animals were sacrificed at 3, 6 and 12 weeks following surgery with anintravenous lethal injection of anesthetic. The right hind limb of eachwas stripped of soft tissue and muscle and fixed in 10% phosphatebuffered formalin for a minimum of 72 hours with changes every 24 hours.The femoral and tibial bone tunnels were isolated using a saw anddecalcified in 10% formic acid—formalin solution. The femur and tibialtunnels were sectioned into 2-3 mm slices from the joint space to theouter cortex and placed into cassettes for paraffin embedding.Five-micron thick sections were cut on a microtome and stained withhematoxylin and eosin for microscopic analysis.

After 3 weeks of ultrasound treatment there are marked differencesvisible between histology images of tissue from the control animals(FIG. 20A) and the ultrasound-treated animals (FIG. 20B). In theultrasound-treated grafts there is cellular infiltration of fibroustissue into the tendon in between the tendon fascicles. There isneo-angiogenesis/vascularity shown in the 20× magnification image,indicated by the arrows. The graft is highly cellular and the cells areplump active (matrix producing) cells. By contrast, the control samples(FIG. 20A) show no evidence of vascularity, the cells within the graftare necrotic, and the tendon is starting to degenerate.

After 6 weeks of ultrasound there is extensive neoangiogenesis in thegraft, as shown in FIG. 21B. The black dots in the 2× magnificationpicture are all new blood vessels. The red blood cells within thesevessels can be seen in the 10× magnification image. At 20× magnificationthere are viable cells throughout the graft and there is new bonedeposition and Sharpey's fibres at the interface of the graft and thebone tunnel. The Sharpey's fibres are spicules of bone that anchor thegraft into the bone tunnel. By contrast, the control histology imagesshown in FIG. 21A show very little evidence of vascularity. The cellswithin the tendon body are very sparse and there is little evidence ofSharpey's fibres at the bone tendon interface. After six weeks ofultrasound treatment the angiogenic response is very pronounced that theintra-articular section of the graft and the bone marrow contained newblood vessels, as shown in FIGS. 21C and 21D, respectively.

At 12 weeks, the intra-articular section of the graft in the controlgroup, shown in FIG. 22A is essentially dead, with very few cells andblood vessels. By contrast, the ultrasound treated graft, shown in FIG.22B, is highly cellular and contains functional blood vessels containingred blood cells. Photomicrographs of the treated graft show that thereis a mature tissue at the bone tendon interface with healthy activecells after ultrasound treatment, shown in FIG. 22D. There are manySharpey's fibres infiltrating the graft, which will provide increasedstrength. By contrast, photomicrographs of the control graft, FIG. 22Cshow few cells, which are producing a loose fibrous tissue, and fewSharpey's fibres at the bone tendon interface.

Example 2

Hartley strain guinea pigs that spontaneously develop osteoarthritis(OA) were used for this study. This strain develops an arthropathologythat mimics human OA between the age of 6 and 12 months of age. The OAis confined to the medial tibia plateau in the early stages of thedisease.

Eight animals were utilized for this study. The animals were 2 months ofage when the study was initiated. The left legs of the animals weretreated with pulsed low intensity ultrasound (1.5 MHz, pulsed at 1 KHz,200 μs burst width) for a period of 4 months. The ultrasound was appliedfor 20 minutes per day, for 5 days per week. The ultrasound transducerwas coupled to the skin with gel on the media side of the left kneeafter first shaving the knee joint. The transducers were held in placeduring treatment with strapping. The animals were terminated at 6 monthsof age after 4 months of treatment.

The ultrasound treated (FIG. 23A) and control (FIG. 23B) knee jointswere dissected and decalcified in 10% formic acid—formalin solution. Theknee joints were then embedded in paraffin. Five-micron thick sectionswere cut on a microtome and stained with toluidine blue for microscopicanalysis. After 4 months of ultrasound treatment there was a markeddifference in the degree/severity of OA between the treated and controlknees. The cartilage on the media tibia plateau of ultrasound treatedknee remained intact, as shown in FIG. 23A, whereas the cartilage on thecontrol knee showed signs of degeneration, as shown in FIG. 23B. Thisobservation (cartilage thinning, defects and surface irregularities) wasconsistently observed in animals that developed OA by 6 months of age.

It will be understood that various modifications can be made to thevarious embodiments of the present invention herein disclosed withoutdeparting from its spirit and scope. For example, various modificationsmay be made in the structural configuration of the placement modules andthe configuration of the components used to excite the ultrasonictransducer. Therefore the above description should not be construed aslimiting the invention by merely as presenting preferred embodiments ofthe invention. Those skilled in the art will envision othermodifications within the scope and spirit of the present invention asdefined by the claims presented below.

1. A method for stimulating growth or healing, or treating pathologies,of connective tissue in mammals in need thereof, comprising: subjectingthe affected connective tissue selected from the group consisting ofcartilage in one or more natural joints of the mammal, ligaments,tendons, fascia, and combinations thereof to noninvasive, low intensitypulsed ultrasound with a substantially single frequency between about 1and about 2 MHz, a pulse width of between about 10 and about 2,000microseconds, a repetition frequency of about 0.10 to about 10 KHz, anda duration sufficient to stimulate growth, healing, or repair of theconnective tissue.
 2. The method of claim 1, wherein the low intensityultrasound has a frequency of around 1.5 MHz.
 3. The method of claim 1,wherein the pulse width is about 200 microseconds.
 4. The method ofclaim 1, wherein the repetition frequency is about 1 KHz.
 5. The methodof claim 1, wherein the connective tissue comprises tissue that hasundergone or is undergoing degeneration as the result of osteoarthritis,tendonosis, or tendonitis, or a combination thereof.
 6. The method ofclaim 5, wherein healing is stimulated without surgical repair ormodification of the tissue.
 7. The method of claim 1, wherein theconnective tissue undergoing treatment has been subjected to surgery onor near the connective tissue.
 8. The method of claim 7, wherein thesurgery comprises repair of flexor or extensor tendons.
 9. The method ofclaim 7, wherein the surgery comprises surgical transfer of a ligamentor tendon or a ligament or tendon weave.
 10. The method of claim 7,wherein the surgery comprises implantation of a scaffold capable ofsupporting tissue repair or regrowth.
 11. The method of claim 10,wherein the scaffold comprises a material having a structuresufficiently porous to allow cell infiltration, and having a surfacesufficient to allow cell adhesion and growth.
 12. The method of claim 7,wherein the surgery comprises repair of a fibrocartilage.
 13. The methodof claim 12, wherein the fibrocartilage is selected from the groupconsisting of damaged lateral or medial meniscus, mandibular meniscus,spinal disc cartilage, and rib cartilage.
 14. The method of claim 1,wherein the connective tissue undergoing treatment comprises one or moreligaments.
 15. The method of claim 14, wherein at least one of theligaments is located in the human knee.
 16. The method of claim 15,wherein the ligaments include the anterior cruciate ligament orposterior cruciate ligament.
 17. The method of claim 15, wherein the oneor more ligaments include a genual ligament or a meniscofemoralligament.
 18. The method of claim 14, wherein the one or more ligamentsinclude a lateral or collateral ligament.
 19. The method of claim 1,wherein the connective tissue undergoing treatment comprises one or moretendons.
 20. The method of claim 19, wherein at least one of the tendonsis located in the human knee.
 21. The method of claim 20, wherein thetendon is one or more of the tendon of quadriceps, gracilis tendon,sartorius tendon, semitendinosis tendon, popliteus tendon, or adductormagnus tendon.
 22. The method of claim 19, wherein the tendon is in thehuman shoulder.
 23. The method of claim 22, wherein the tendon is thesupraspinatus tendon.
 24. The method of claim 1, wherein the connectivetissue is a spinal disc with a degenerative disease.
 25. The method ofclaim 1, wherein the ultrasound is applied to connective tissuefollowing a tissue shrinkage procedure.
 26. The method of claim 25,wherein the tissue shrinkage procedure is selected from the groupconsisting of capsulorraphy and spinal disc shrinkage.
 27. The method ofclaim 1, wherein the connective tissue pathology is tendonitis ortendonosis.
 28. The method of claim 1, wherein the connective tissue hassuffered an acute tear or chronic overuse injury.
 29. The method ofclaim 1, wherein the connective tissue is located in the elbow joint.30. The method of claim 29, wherein the pathology is tennis elbow. 31.The method of claim 1, wherein the connective tissue is located in thefoot.
 32. The method of claim 31, wherein the pathology is plantarfascitis.
 33. The method of claim 1, wherein the connective tissuecomprises fascia.
 34. The method of claim 1, wherein the connectivetissue undergoing treatment is located in the human knee.
 35. The methodof claim 34, wherein the connective tissue comprises the lateral ormedial meniscus.
 36. The method of claim 1, further comprisingadministering to the mammal a pharmacological agent.
 37. The method ofclaim 36, wherein the pharmacological agent is a drug or growth factor.38. The method of claim 36, wherein the growth factor is administered insufficient dosage to increase the rate of repair, the quality of repair,or both.
 39. The method of claim 36, wherein the growth factor isselected from the group consisting of the Transforming Growth Factor.beta. superfamily, Bone Morphogenetic Proteins, Cartilage DerivedMorphogenic Proteins and Growth Differentiation Factors, angiogenicfactors, platelet-derived cell growth factor (PD-LCGF), Platelet DerivedGrowth Factors (PDGF), Vascular Endothelial Growth Factor (VEGF), theEpidermal Growth Factor family, Transforming Growth Factor Alpha(TGF.alpha.), Platelet Derived Growth Factors, e.g. PDGF-A, PDGF-B,PDGF-BB, Fibroblast Growth Factors, e.g. BFGF, Hepatocyte Growth Factors(HGF), Insulin-like Growth Factors, Growth Hormones (GH), Interleukins,Connective Tissue Growth Factors (CTGF), Parathyroid Hormone RelatedProteins (PTHrp), autologous growth factors, and mixtures of at leasttwo of these materials.
 40. The method of claim 1, wherein theultrasound is generated by a plurality of ultrasonic transducers placedin the vicinity of the skin the tissue to be treated.
 41. The method ofclaim 40, wherein the ultrasonic transducers emit ultrasoundsimultaneously or sequentially.
 42. The method of claim 1, wherein theintensity of the ultrasound is less than 100 milliwatts/cm².
 43. Themethod of claim 1 wherein subjecting the affected connective tissue tothe low intensity pulsed ultrasound stimulates healing, growth, orrepair of the connective tissue substantially without applying thermalenergy.
 44. A method for stimulating connective tissue in mammals inneed thereof, the method comprising: subjecting the affected connectivetissue selected from the group consisting of cartilage in one or morenatural joints of the mammal, ligaments, tendons, fascia, andcombinations thereof to noninvasive, low intensity pulsed ultrasoundwith a substantially single frequency between about 1 and about 2 MHz, apulse width of between about 10 and about 2,000 microseconds, and arepetition frequency of about 0.10 to about 10 KHz.
 45. A method forstimulating connective tissue in mammals in need thereof, the methodcomprising: subjecting the affected connective tissue selected from thegroup consisting of cartilage in one or more natural joints of themammal, ligaments, tendons, fascia, and combinations thereof tononinvasive, low intensity pulsed ultrasound with a substantially singlefrequency between about 1 and about 2 MHz, a pulse width of betweenabout 100 and about 300 microseconds, and a repetition frequency ofabout 0.5 to about 2.5 KHz.
 46. A method for stimulating connectivetissue in mammals in need thereof, the method comprising: subjecting theaffected connective tissue selected from the group consisting ofcartilage in one or more natural joints of the mammal, ligaments,tendons, fascia, and combinations thereof to noninvasive, low intensitypulsed ultrasound with a substantially single frequency, a pulse widthof between about 100 and about 300 microseconds, and a repetitionfrequency of about 0.5 to about 2.5 KHz.